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IntroductionMultiple myeloma (MM) almost exclusively develops in the bone marrow and generates devastating bone destruction by osteoclasts (OCs) recruited around MM cells. A marked stimulation of osteoclastic bone resorption causes debilitating clinical symptoms, including intractable bone pain, disabling multiple fractures, and hypercalcemia. The severity of bone disease correlates with the tumor burden and is one of the major parameters in widely used Durie and Salmon clinical staging system. It is of note that the aggressive features of MM bone lesions have significantly contributed to its poor prognosis despite the recent development of intensive chemotherapeutic regimens. 1,2 Therefore, elucidation of the molecular mechanism of bone destruction and tumor progression is essential for the development of effective therapies to improve survival as well as quality of life of patients with MM.Interactions between receptor activator of nuclear factorkappaB (RANK) expressed on the surface of the OC lineage cells and RANK ligand expressed on stromal cells play a key role in the development and activation of OCs, whereas osteoprotegerin, a decoy receptor for RANK ligand secreted from stromal cells, inhibits RANK ligand-RANK signaling. 3-8 MM cells stimulate osteoclastogenesis by triggering a coordinated increase in RANK ligand and decrease in osteoprotegerin in bone marrow (BM) stromal cells. [9][10][11] We and others have demonstrated that osteoclastogenic CC chemokines macrophage inflammatory protein 1␣ (MIP-1␣) and MIP-1␤ are secreted from most of MM cells and play a critical role in the development of MM bone lesions. [12][13][14][15][16][17][18] These chemokines act on MM cells in an autocrine/paracrine fashion and enhance MM cell adhesion to stromal cells through activation of integrins, including very late antigen-4 (VLA-4). The interaction between MM and stromal cells then induces RANK ligand expression by stromal cells, leading to OC differentiation and activation. 12 Almost exclusive development of MM in the BM suggests that the BM microenvironment supports MM cell growth and survival. Among cell components in the BM, roles of stromal cells in MM cell growth and survival have been extensively studied. When cocultured with MM cells, stromal cells are stimulated to produce interleukin 6 (IL-6), which promotes proliferation of MM cells and prevents them from apoptosis induced by anticancer agents. [19][20][21] Other than stromal cells, OCs induced by MM cells are among major cellular components of the BM microenvironment. Administration of inhibitors of osteoclast activity, including bisphosphonates, RANK-Fc, and osteoprotegerin, not only prevented MMinduced bone destruction but also interfered with tumor progression in animal models of MM. 9,22-25 Repeated administration of bisphosphonates has also been reported to reduce the tumor burden without chemotherapy in a portion of patients with MM. 26 These observations raise a possibility that an interaction between OCs and MM Materials and methods ChemicalsThe f...

Background & Aims It is important to increase our understanding of gustatory detection of dietary fat and its contribution to fat preference. We studied the roles of the fat taste receptors CD36 and GPR120 and their interactions via Ca2+ signaling in fungiform taste bud cells (TBC). Methods We measured Ca2+ signaling in human TBC, transfected with small interfering RNAs (siRNAs) against mRNAs encoding CD36 and GPR120 (or control siRNAs). We also studied Ca2+ signaling in TBC from CD36−/− mice and from wild-type lean and obese mice. Additional studies were conducted with mouse enteroendocrine cell line STC-1 that express GPR120 and stably transfected with human CD36. We measured release of serotonin and GLP-1 from human and mice TBC in response to CD36 and GPR120 activation. Results High concentrations of linoleic acid induced Ca2+ signaling via CD36 and GPR120 in human and mice TBC as well as in STC-1 cells, whereas low concentrations induced Ca2+ signaling via only CD36. Incubation of human and mice fungiform TBC with lineoleic acid downregulated CD36 and upregulated GPR120 in membrane lipid rafts. Obese mice had decreased spontaneous preference for fat. Fungiform TBC from obese mice had reduced Ca2+ and serotonin responses but increased release of GLP1, along with reduced levels of CD36 and increased levels of GPR120 in lipid rafts. Conclusions CD36 and GPR120 have non-overlapping roles in TBC signaling during oro-gustatory perception of dietary lipids; these are differentially regulated by obesity.

IntroductionMultiple myeloma (MM) almost exclusively develops and expands in the bone marrow (BM) and generates devastating bone destruction by osteoclasts (OCs). The bone destruction causes debilitating clinical symptoms including intractable bone pain, disabling multiple fractures, and hypercalcemia. The severity of bone disease correlates with the tumor burden and is one of the major parameters in the Durie and Salomon clinical staging system. Furthermore, the aggressive features of MM bone lesions have contributed significantly to its poor prognosis despite the recent development of intensive chemotherapeutic regimens. 1,2 Therefore, elucidation of the molecular mechanism of bone destruction and tumor progression is essential for the development of effective therapies to improve survival as well as quality of life of patients with MM.Interaction between receptor activator of nuclear factor-B (RANK) expressed on the surface of cells of osteoclastic lineage and RANK ligand expressed on stromal cells plays a key role in the development and activation of OCs, whereas osteoprotegerin, a decoy receptor for RANK ligand secreted from stromal cells, inhibits RANK ligand-RANK signaling. 3,4 MM cells stimulate osteoclastogenesis by triggering a coordinated increase in RANK ligand and decrease in osteoprotegerin in the BM. [5][6][7] We and others have demonstrated that osteoclastogenic CC chemokines macrophage inflammatory protein 1␣ (MIP-1␣) and MIP-1␤ are secreted from most MM cells and play a critical role in the development of MM bone lesions. [8][9][10][11][12] These chemokines directly act on MM cells in an autocrine/paracrine fashion and enhance MM cell adhesion to stromal cells through activation of integrins including very late antigen 4. The interaction between MM cells and stromal cells induces RANK ligand expression by stromal cells, leading to OC differentiation and activation. 8 Furthermore, OCs enhance MM cell growth and survival through a cell-to-cell contact-dependent mechanism that is partially mediated by OC-derived interleukin 6 (IL-6) and osteopontin. 13,14 These observations suggest that interactions of MM cells and OCs form a vicious cycle leading to extensive bone destruction and MM cell expansion.Along with enhanced bone resorption, mineralization is impaired in MM bone lesions. Radiographic examinations show radiolucent lesions without calcification known as "punched-out" lesions. Analyses of bone turnover in patients with MM by biochemical bone markers also suggested an imbalance of bone turnover with enhanced bone resorption and suppressed bone formation. 15 However, the mechanisms of impaired bone formation in bone lesions of patients with MM remain poorly understood.A canonical Wingless-type (Wnt) signaling pathway has been shown to play an important role in osteoblast differentiation. Wnts are secreted cysteine-rich glycoproteins, known as regulators of the differentiation of hematopoietic and mesenchymal cells as well as embryonic development. [16][17][18] Wnt proteins bind to the Frizzle...